Genome-scale clustered regularly interspaced short palindromic repeats screen identifies nucleotide metabolism as an actionable therapeutic vulnerability in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common malignancy that develops in patients with ataxia-telangiectasia, a cancer-predisposing inherited syndrome characterized by inactivating germline ATM mutations. ATM is also frequently mutated in sporadic DLBCL. To investigate lymphomagenic mechanisms and lymphoma-specific dependencies underlying defective ATM, we applied RNA sequencing and genome-scale loss-of-function clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 screens to systematically interrogate B-cell lymphomas arising in a novel murine model (Atm-/-nu-/-) with constitutional Atm loss, thymic aplasia but residual T-cell populations.

Bi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly.

Telomere maintenance 2 (TELO2), Tel2 interacting protein 2 (TTI2), and Tel2 interacting protein 1 (TTI1) are the three components of the conserved Triple T (TTT) complex that modulates activity of phosphatidylinositol 3-kinase-related protein kinases (PIKKs), including mTOR, ATM, and ATR, by regulating the assembly of mTOR complex 1 (mTORC1). The TTT complex is essential for the expression, maturation, and stability of ATM and ATR in response to DNA damage. TELO2- and TTI2-related bi-allelic autosomal-recessive (AR) encephalopathies have been described in individuals with moderate to severe intellectual disability (ID), short stature, postnatal microcephaly, and a movement disorder (in the case of variants within TELO2).

Biallelic Mutation of and Additional Likely "In Cis" Sequence Change in Ataxia with Oculomotor Apraxia Type 2.

Ataxia with oculomotor apraxia type 2 (AOA2) is a slowly progressive, autosomal recessive disease characterized by the triad of ataxia, oculomotor apraxia, and sensorimotor neuropathy. The genetic basis of AOA2 is biallelic mutation of the gene, resulting in reduced or absent senataxin, a DNA/RNA repair protein essential for genomic stability. In this case report, we described a case of AOA2 with two clear pathogenic mutations, one of which is novel.

Genotype, extrapyramidal features, and severity of variant ataxia-telangiectasia.

Objective: Variant ataxia-telangiectasia is caused by mutations that allow some retained ataxia telangiectasia-mutated (ATM) kinase activity. Here, we describe the clinical features of the largest established cohort of individuals with variant ataxia-telangiectasia and explore genotype-phenotype correlations.

Methods: Cross-sectional data were collected retrospectively.

Degradation of a Novel DNA Damage Response Protein, Tankyrase 1 Binding Protein 1, following Adenovirus Infection.

Infection by most DNA viruses activates a cellular DNA damage response (DDR), which may be to the detriment or advantage of the virus. In the case of adenoviruses, they neutralize antiviral effects of DDR activation by targeting a number of proteins for rapid proteasome-mediated degradation. We have now identified a novel DDR protein, tankyrase 1 binding protein 1 (TNKS1BP1) (also known as Tab182), which is degraded during infection by adenovirus serotype 5 and adenovirus serotype 12.

A Hypomorphic PALB2 Allele Gives Rise to an Unusual Form of FA-N Associated with Lymphoid Tumour Development.

Patients with biallelic truncating mutations in PALB2 have a severe form of Fanconi anaemia (FA-N), with a predisposition for developing embryonal-type tumours in infancy. Here we describe two unusual patients from a single family, carrying biallelic PALB2 mutations, one truncating, c.1676_1677delAAinsG;(p.

Identification of the first ATRIP-deficient patient and novel mutations in ATR define a clinical spectrum for ATR-ATRIP Seckel Syndrome.

A homozygous mutational change in the Ataxia-Telangiectasia and RAD3 related (ATR) gene was previously reported in two related families displaying Seckel Syndrome (SS). Here, we provide the first identification of a Seckel Syndrome patient with mutations in ATRIP, the gene encoding ATR-Interacting Protein (ATRIP), the partner protein of ATR required for ATR stability and recruitment to the site of DNA damage. The patient has compound heterozygous mutations in ATRIP resulting in reduced ATRIP and ATR expression.

Very mild presentation in adult with classical cellular phenotype of ataxia telangiectasia.

Background: The major clinical feature of ataxia telangiectasia (A-T) is severe progressive neurodegeneration with onset in infancy. This classical A-T phenotype is caused by biallelic null mutations in the ATM gene, leading to the absence of ATM protein and increased cellular radiosensitivity. We report an unusual case of A-T in a 41-year-old mother, A-T210, who had very mild neurological symptoms despite complete loss of ATM protein.

Serotype-specific inactivation of the cellular DNA damage response during adenovirus infection.

Adenovirus type 5 (Ad5) inactivates the host cell DNA damage response by facilitating the degradation of Mre11, DNA ligase IV, and p53. In the case of p53, this is achieved through polyubiquitylation by Ad5E1B55K and Ad5E4orf6, which recruit a Cul5-based E3 ubiquitin ligase. Recent evidence indicates that this paradigm does not apply to other adenovirus serotypes, since Ad12, but not Ad5, causes the degradation of TOPBP1 through the action of E4orf6 alone and a Cul2-based E3 ubiquitin ligase.

Modeling ATM mutant proteins from missense changes confirms retained kinase activity.

Ataxia-telangiectasia mutated (ATM) is the gene mutated in the cancer-predisposing disorder ataxia-telangiectasia (A-T). We modeled ATM sequence variants identified in UK A-T patients to determine the stability and kinase activity of the resulting proteins as well as the distribution of these mutations across the coding region. Of 20 missense changes modeled, 10 proteins showed ATM kinase activity and 10 showed none.

The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage.

The biological response to DNA double-strand breaks acts to preserve genome integrity. Individuals bearing inactivating mutations in components of this response exhibit clinical symptoms that include cellular radiosensitivity, immunodeficiency, and cancer predisposition. The archetype for such disorders is Ataxia-Telangiectasia caused by biallelic mutation in ATM, a central component of the DNA damage response.

Pathogenic ATM mutations occur rarely in a subset of multiple myeloma patients.

Ataxia Telangiectasia (A-T) patients have biallelic inactivation of the ATM gene and exhibit a 200-fold-increased frequency of lymphoid tumours. ATM mutations have been found in a number of adult lymphoid malignancies but there is no data on the occurrence of ATM mutations in multiple myeloma tumours. The purpose of our work was to investigate the occurrence of ATM mutations in multiple myeloma and to this end we screened 45 sporadic cases for ATM mutations using denaturing high-performance liquid chromatography analysis and DNA sequencing.

RIDDLE immunodeficiency syndrome is linked to defects in 53BP1-mediated DNA damage signaling.

Cellular DNA double-strand break-repair pathways have evolved to protect the integrity of the genome from a continual barrage of potentially detrimental insults. Inherited mutations in genes that control this process result in an inability to properly repair DNA damage, ultimately leading to developmental defects and also cancer predisposition. Here, we describe a patient with a previously undescribed syndrome, which we have termed RIDDLE syndrome (radiosensitivity, immunodeficiency, dysmorphic features and learning difficulties), whose cells lack an ability to recruit 53BP1 to sites of DNA double-strand breaks.

Atypical presentation of ataxia-oculomotor apraxia type 1.

A subgroup of autosomal recessive cerebellar ataxias (ARCAs) associated with oculomotor apraxia (OMA) and other variable features has been reported. Ataxia-oculomotor apraxia types 1 and 2 (AOA1 and AOA2) belong to this subgroup and have been described in adults with early onset cerebellar ataxia. AOA1 is associated with oculomotor apraxia, severe sensorimotor neuropathy, choreiform movements, cognitive impairment, and cerebellar atrophy at an early age.

The interaction of the hnRNP family member E1B-AP5 with p53.

Adenovirus early region 1B-associated protein 5, E1B-AP5, a member of the heterogeneous nuclear ribonucleoprotein (hnRNP) family, was originally isolated on the basis of its ability to bind to the adenovirus 5 early region1B55K protein. Here, it has been demonstrated that E1B-AP5 interacts with mutant and wild-type p53 from human cells in pull-down assays using GST-E1B-AP5. This interaction has been confirmed by co-immunoprecipitation studies and pull-down experiments with in vitro translated E1B-AP5 and GST-p53.

The ataxia-oculomotor apraxia 1 gene product has a role distinct from ATM and interacts with the DNA strand break repair proteins XRCC1 and XRCC4.

Ataxia-oculomotor apraxia 1 (AOA1) is an autosomal recessive neurodegenerative disease that is reminiscent of ataxia-telangiectasia (A-T). AOA1 is caused by mutations in the gene encoding aprataxin, a protein whose physiological function is currently unknown. We report here that, in contrast to A-T, AOA1 cell lines exhibit neither radioresistant DNA synthesis nor a reduced ability to phosphorylate downstream targets of ATM following DNA damage, suggesting that AOA1 lacks the cell cycle checkpoint defects that are characteristic of A-T.

Adult-onset ataxia telangiectasia due to ATM 5762ins137 mutation homozygosity.

Ataxia telangiectasia (A-T) is an autosomal recessive neurodegenerative disorder that arises because of mutations in the ATM gene. The 5762ins137 A-->G point mutation activates a cryptic splice donor site resulting in a 137 bp intronic insert being aberrantly spliced into the ATM transcript. However, normal ATM transcript also is produced from this affected allele, albeit at significantly reduced levels.

Microarray analysis reveals that TP53- and ATM-mutant B-CLLs share a defect in activating proapoptotic responses after DNA damage but are distinguished by major differences in activating prosurvival responses.

The ATM/p53-dependent DNA damage response pathway plays an important role in the progression of lymphoid tumors. Inactivation of the ATM or TP53 gene is frequent in B-cell lymphocytic leukemia (B-CLL) and leads to aggressive disease. Although the ATM and p53 pathways overlap, they are not congruent, and it is unclear how the mechanism of tumor progression differs between ATM- and p53-deficient tumors.

Ataxia telangiectasia mutated-deficient B-cell chronic lymphocytic leukemia occurs in pregerminal center cells and results in defective damage response and unrepaired chromosome damage.

B-cell chronic lymphocytic leukemia (B-CLL) is a heterogeneous disease involving more than one molecular mechanism that leads to the transformation of CD5(+) B cells at either the pregerminal or postgerminal center stage of differentiation. It was previously demonstrated that ataxia telangiectasia mutated (ATM) gene mutations can occur in B-CLL and cause a defect in the p53 pathway. Here the role of ATM mutations in the pathogenesis of B-CLL is addressed.